The long-term objective of this project is to discover new, practical methods for introducing trifluoromethyl groups to complex molecules. The catalytic installation of trifluoromethyl moieties is a largely unsolved problem in organic chemistry. Due to the rising demand for fluorinated pharmaceutical targets, the development of such a method is an important, current, unmet synthetic need. An ideal method for installing a trifluoromethyl group should be both mild and general, in addition to using atom-economical and environmentally benign sources of the CF3 group. To date, there are no catalytic cross-coupling reactions involving the installation of trifluoromethyl groups that are general or widely employed. The absence of catalytic trifluoromethylation methods parallels our lack of knowledge about the reactivity of transition metal complexes containing CF3 ligands;consequently the proposed studies are aimed to unearth systems that catalyze coupling of trifluoromethyl groups and the underlying fundamental chemistry that controls these reactions. There are three specific aims: 1) to develop a copper-catalyzed method for the trifluoromethylation of aromatic halides in which the trifluoromethyl anion is generated from the copper-catalyzed decarboxylation of trifluoroacetate;2) to develop a dual catalyst method for trifluoromethylation of aryl halides that capitalizes on the reductive elimination of aryl-CF3 from a Pd center;3) to develop a catalytic aromatic trifluoromethylation using fluoroform as the source of the CF3 group. To realize these goals, known copper catalysts will be synthesized and tested, first for their ability to catalyze the decarboxylation of trifluoroacetate, and then for their ability to catalyze the trifluoromethylation of aryl halides. This information can then be applied to a dual-catalyst system, where copper catalyzes the decarboxylation of trifluoroacetate and palladium catalyzes the cross-coupling. A successful dual-catalytic system would represent two major achievements: the development of a general aryl-trifluoromethylation method and the first exploitation of a reductive elimination of an aryl-CF3 from a Pd center in a catalytic system. Furthermore, establishing the viability of this reductive elimination in a catalytic setting will vastly broaden the scope of the reaction and new substrates will be tested. In the final stage of this project, fluoroform, a major by-product of the Teflon industry, will be activated by a palladium catalyst and applied to a catalytic reaction. To do so, the stoichiometric activation of fluoroform will be attempted using known and characterized reaction intermediates followed by attempts at the catalytic system. PUBLIC HEALTH RELEVANCE: The addition of fluorine to drug targets often imparts valuable qualities to the molecule, such as bioavailability and stability. The ability to synthesize new pharmaceutical molecules is limited by the synthetic methods that scientists can employ. As such, it is important to develop methods for introducing fluorine to complex molecules such that new potential drugs can be quickly synthesized and evaluated.